Cameron Thomas, Pharm.D.PGY2 Clinical Pharmacogenetics Resident

St. Jude Children’s Research HospitalFebruary 1, 2018

CYP2C19-Proton Pump Inhibitors

Objectives: CYP2C19-PPI Implementation

Review the pharmacogenetics of PPIs

Discuss the relationships between PPI pharmacokinetics, intragastric pH, clinical outcomes, and CYP2C19 genotype

Consider the medication safety implications for PPI prescribing based on CYP2C19 genotype

Proton Pump Inhibitor Classification

PPI

First Generation

Omeprazole

Pantoprazole

Lansoprazole

Second Generation

Esomeprazole

Rabeprazole

Dexlansoprazole

PPIs are metabolized by CYP2C19(rabeprazole to a lesser extent)

Hagymasi, et al. Pharmacogenomics. 2011;12:873-88.

90%

Inactive

Active

Rationale for Implementation: All PPIs are designated CPIC Level B

www.cpicpgx.org/

Dutch Pharmacogenetics Working Group Recommendations for CYP2C19-PPIs

Phenotype Prescribing Recommendation

Omeprazole

PM No therapeutic recommendation

IM No therapeutic recommendation

UM H. pylori: ↑ dose by 100-200%

Other: Consider dose ↑ by 100-200%

Pantoprazole

PM No therapeutic recommendation

IM No therapeutic recommendation

UM H. pylori: ↑ dose by 400%

Other: Consider dose ↑ by 400%Swen, et al. Clin Pharmacol Ther. 2011;89:662-73.

Dutch Pharmacogenetics Working Group Recommendations for CYP2C19-PPIs

Phenotype Prescribing Recommendation

Lansoprazole

PM No therapeutic recommendation

IM No therapeutic recommendation

UM H. pylori: ↑ dose by 200%

Other: Consider dose ↑ by 200%

Esomeprazole

PM No therapeutic recommendation

IM No therapeutic recommendation

UM H. pylori: ↑ dose by 50-100%

Other: Consider dose ↑ by 50-100%Swen, et al. Clin Pharmacol Ther. 2011;89:662-73.

Dutch Pharmacogenetics Working Group Recommendations for CYP2C19-PPIs

Phenotype Prescribing Recommendation

Rabeprazole

PM No therapeutic recommendation

IM No therapeutic recommendation

UM No Therapeutic recommendation

Dexlansoprazole (not addressed in guidelines)

PM N/A

IM N/A

UM N/A

Swen, et al. Clin Pharmacol Ther. 2011;89:662-73.

1. RELATING PPI PHARMACODYNAMICS TO CLINICAL OUTCOMES

Increasing intragastric pH to at least 3 for 18 hours a day for 4 weeks is necessary for duodenal ulcer healing

Burget D, et al. Gastroenterology. 1990;99:345-51.

Contour plots for the predicted relationship between duodenal ulcer healing and acid suppression at 2 (A), 4 (B), and 8 (C) weeks of therapy.

Correlation between the healing rate of erosive esophagitis at 8 weeks and the duration (hr) that intragastric pH is maintained > 4.0

r = 0.87 (p < 0.05)

Bell N, et al. Digestion. 1992;51(suppl 1):59-67.

2. CYP2C19 GENOTYPE IS ASSOCIATED WITH SYSTEMIC EXPOSURE

CYP2C19 UM (*17/*17) phenotype associated with lower mean plasma lansoprazole concentrations vs. NMs (*1/*1)

Gumus, et al. Eur J Clin Pharmacol 2012;68:629-36

*17*17: Mean Cplasma 70% lower

*2*2: Mean Cplasma 6.9-fold higher

Mean plasma concentrations of omeprazole are significantly lower in CYP2C19 UMs vs. NMs

Payan, et al. Daru. 2014;22:81-90.Baldwin, et al. Br J Clin Pharmacol. 2008;65:767-74.

Plasma concentrations of omeprazole are lower in CYP2C19 NMs compared to IM and PMs

Furuta, et al. Clin Pharmacol Ther. 1999;65:552-61.

Mean AUC value in PMs ~13x higher than NM group

NM

2. CYP2C19 GENOTYPE IS ASSOCIATED WITH PPI SYSTEMIC EXPOSURE

CYP2C19 No Function Allele

CYP2C19 *17 allele

Park, et al. JKMS. 2017;32:726-36.Hunfeld, et al. BJCP. 2008;65:752-60.Roman, et al. Pharmacogenomics. 2014;15:1893-901.Gawronska, et al. Eur J Clin Pharmacol. 2012;68:1267-74.

3. CYP2C19 GENOTYPE IS ASSOCIATED WITH INTRAGASTRIC PH VARIABILITY

Positive correlation between mean intragastric pH and omeprazole AUC

Single dose study of omeprazole 20 mg daily in healthy volunteers

Furuta, et al. Clin Pharmacol Ther. 1999;65:552-61.

CYP2C19 NM (n = 5)

CYP2C19 IM (n = 4)

CYP2C19 PM (n = 6)

CYP2C19*17 allele carriers with GERD spent more time with esophageal pH < 4 (undesirable outcome)

Retrospective cohort of 74 children who were refractory to PPI therapy

*1/*17, *17/*17

Franciosi, et al. J Clin Pharmacol. 2018;58(1):89-96.

4. RELATING CYP2C19 PHENOTYPE TO CLINICAL OUTCOMES

CYP2C19 NM were at higher risk of being refractory to PPItherapy for erosive esophagitis

Favors PMFavors NM

Ichikawa, et al. J Gastroenterol Hepatol. 2016;31:716-26.

Healing rate of erosive esophagitis was significantly lower in NMs compared to PMs after 8 weeks of LAN 30 mg daily

Kawamura, et al. Aliment Pharmacol Ther. 2003;17:965-73.

Healing rate (%) by endoscopy after 8 weeks of treatment

45.8%

67.9%

84.6%

Furuta, et al. Clin Pharmacol Ther. 2002;72:453-60.

Treatment dose = LAN 30 mg daily x 8 weeks

CYP2C19 phenotype associated with endoscopic and symptomatic relapse of erosive esophagitis during

maintenance therapy with LAN 15 mg daily

Kawamura, et al. J Gastroenterol Hepatol. 2007;22:222-6.Furuta, et al. Eur J Clin Pharmacol. 2009;65:693-8.

NM

Symptomatic recurrence of erosive esophagitis during maintenance therapy with LAN 15 mg/d occurred within 2-4 weeks after step-down of daily dose

CYP2C19 NM: lower remission

rates

4. RELATING CYP2C19 PHENOTYPE TO CLINICAL OUTCOMES

1. CYP2C19 NMs at increased risk of refractoriness to PPIs for erosive esophagitis treatment

2. CYP2C19 phenotype associated with endoscopic and symptomatic relapse of erosive esophagitis during maintenance therapy with Lansoprazole 15 mg daily

Overview of the safety of PPIs

• Short-term side effects include: HA, diarrhea, nausea

– Class effect

– Incidence rates from 1 – 3%

• Safety concerns with long-term PPI use

– Pulmonary: pneumonia, upper respiratory tract infections

– GI: Clostridium difficile-associated diarrhea

– Skeletal: osteoporosis, hip and vertebral fracture

– Neuro: visual disturbances

– Renal: Interstitial nephritis

Thompson, et al. World J Gastroenterol. 2010;16(19):2323-30.Cunningham, et al. J Hosp Infect. 2003;54:243-5.

Lin, et al. Osteoporos Int. 2018;29:153-62.

5. PPI USE AND RESPIRATORY TRACT INFECTIONS

PPIs-Pneumonia: Proposed Mechanism

↑ intragastric pH

Bacterial colonization of stomach

Pulmonary micro-aspiration

Lung colonization

PPI administration Thomson, et al. World J Gastroenterol. 2010;16(19):2323-30.Lima, et al. J Pediatr. 2013;163:686-91.

↑ susceptibility to respiratory tract infections

PPI use associated with increased risk of community-acquired pneumonia in adult patients

Johnstone, et al. Aliment Pharmacol Ther. 2010;31(11):1165-77.

Studies: 6 case-control studies

Increased risk of CAP associated with newly prescribed PPIs

Johnstone, et al. Aliment Pharmacol Ther. 2010;31(11):1165-77.

Newly prescribed:< 30 days

Chronic user:> 30 days

Highest risk of CAP occurs within 7 days of starting PPI therapy

Gulmez, et al. Arch Intern Med. 2007;167(9):950-5.

0-7 days: OR, 5.0; 95% CI, 2.1-11.7

>84 days: OR, 1.3; 95% CI, 1.2-1.4

Temporal relationship between start of PPI use and CAP risk

Use of acid-suppressive medication was associate with increased risk of hospital-acquired pneumonia in non-ventilated patients

Herzig, et al. JAMA. 2009;301(20):2120-8.

Primary outcome: hospital-acquired PNA (defined by ICD-9 codes) for bacterial PNA listed as a secondary discharge diagnosis

Addition of LAN to existing asthma therapy did not improve symptoms, but was associated with higher incidence of respiratory adverse events

compared to placebo

Holbrook, et al. JAMA. 2012;307(4):373-81.

Design: randomized, placebo-controlled clinical trial that compared LAN with placebo in children with poor asthma control who were receiving inhaled corticosteroid treatment

No significant difference

Association of CYP2C19 polymorphisms and lansoprazole-associated respiratory adverse effects

Design

• Retrospective analysis of Holbrook, et al. 2012

Objective

• Determine whether CYP2C19 genotype associates with lansoprazole-associated adverse event frequency

Patients (n = 279; pediatrics)

• Poor asthma control while on inhaled corticosteroids

• Drug therapy: 1) placebo or 2) LAN (weight-based) x24 weeks

• Research staff conducted structured interviews using a questionnaire to determine the presence of: upper respiratory tract infections, ST, strep throat, bronchitis, PNA, ear infection, and acute sinusitis

• Genotyping: *2, *3, *8, *9, *17 Lima, et al. J Pediatr. 2013;163(3):686-91.

CYP2C19 PM+IM, but not NM phenotype was associated with increased risk of upper respiratory tract infections

Lima, et al. J Pediatr. 2013;163(3):686-91.

PM + IM

NM

↑ risk compared with placebo

Risk was not significantly different compared with placebo

Mean + SD plasma concentrations of LAN 30 mg/d were higher in PM+IMs (n = 23) compared with NMs (n = 33)- PM+IM: 207 + 179 ng/mL- NM: 132 + 141 ng/mL- p = 0.04

6. PPI USE AND SKELETAL DISORDERS

Any event

Osteoporosis

Hip Fracture

Vertebral Fracture

Stroke patients who used PPIshad a higher incidence of osteoporosis, hip fracture, and vertebral fracture compared with those who did not use PPIs

Lin, et al. Osteoporos Int. 2018;29:153-62.

FDA-labeled Prescribing Recommendations (non-pharmacogenetics guided dosing) by Indication

Indication Omeprazole Lansoprazole Pantoprazole

Duodenal ulcer 20 mg daily x 4 weeks 15 mg daily x 4 weeks

Gastric ulcer 40 mg daily x 4-8 weeks 30 mg daily x 8 weeks

GERD (symptomatic)Pediatric (1-16 YOA)Pediatric (1-11 YOA)

20 mg daily x 4 weeks5-<10 kg: 5 mg daily x 4 w

10-<20 kg: 10 mg daily x 4w> 20 kg: 20 mg daily x 4 w

15 mg daily x 8 weeks< 30 kg: 15 mg daily x12 w> 30 kg: 30 mg daily x12 w

Erosive esophagitisPediatric (1-16 YOA)Pediatric (1-11 YOA)

Pediatric (> 5 YOA)

20 mg daily x 4-8 weeks5-<10 kg: 5 mg daily x 4-8 w

10-<20 kg: 10 mg daily x 4-8 w> 20 kg: 20 mg daily x 4-8 w

30 mg daily x 8 weeks< 30 kg: 15 mg daily x12 w> 30 kg: 30 mg daily x12 w

40 mg daily x 8 weeks15-<40 kg: 20 mg daily x8 w

> 40 kg: 40 mg daily x8 w

Maintenance of healing of erosive esophagitis

Pediatric (1-16 YOA)

20 mg daily5-<10 kg: 5 mg daily

10-<20 kg: 10 mg daily> 20 kg: 20 mg daily

15 mg daily 40 mg daily

CYP2C19-PPIs: Conclusions

CYP2C19 genotype is associated with PPI systemic exposure

CYP2C19 RM/UM phenotypes are associated with undesirable pH outcomes

CYP2C19 NM phenotype is associated with lower healing rates of erosive esophagitis vs. PM phenotype

There may be medication safety implications for CYP2C19phenotype-guided PPI prescribing

Cameron Thomas, Pharm.D.PGY2 Clinical Pharmacogenetics Resident

St. Jude Children’s Research HospitalFebruary 1, 2018

CYP2C19-Proton Pump Inhibitors